H.sub.3 receptor sites are known and are of current interest to those skilled in the art--for example, see: West, Jr. et al., "Biexponential Kinetics of (R)-.alpha.-[.sup.3 H]Methylhistamine Binding to the Rat Brain H.sub.3 Histamine Receptor", Journal of Neurochemistry, Vol. 55, No. 5, pp. 1612-1616, 1990; West, Jr. et al., "Identification of Two H.sub.3 -Histamine Receptor Subtypes", Molecular Pharmacology, 38:610-613; and Korte et al., "Characterization and Tissue Distribution of H.sub.3 Histamine Receptors in Guinea Pigs by N.sup..alpha. -Methylhistamine", Biochemical and Biophysical Research Communications, Vol. 168, No. 3, pp. 979-986.
Arrang et al. in U.S. Pat. No 4,767, 778 (Issued Aug. 30, 1988) disclose a pharmaceutical composition containing a histamine derivative of the formula: ##STR2## wherein each of R.sub.1, R.sub.2, and R.sub.4, represents a hydrogen or a methyl, or R.sub.1 and R.sub.2 taken together represent a methylene, and R.sub.3 is a hydrogen, a methyl or a carboxy, with the proviso that R.sub.1, R.sub.2, R.sub.3, and R.sub.4 are not simultaneously methyl groups. It is disclosed that the derivatives behave as complete agonists of the H.sub.3 receptors in rat brain and produce a maximal inhibition of release identical to that induced by histamine (approximately 60%). It is also disclosed that the histamine derivatives powerfully inhibit the release and synthesis of histamine by very selectively stimulating the H.sub.3 receptors. Consequently, according to Arrang et al., the derivatives are likely to decrease histaminergic transmission in the digestive tract and in the nervous, cardiovascular and immune systems. Arrang et al. disclose that the derivatives can be used in therapy as a drug having sedative effects, as a sleep regulator, anticonvulsant, regulator of hypothalamo-hypophyseal secretion, antidepressant, and modulator of cerebral circulation. According to Arrang et al., inhibition of the release of inflammation messengers in various allergic conditions (e.g., asthma) is expected to result from stimulation of the H.sub.3 receptors of the lung. It is further disclosed that the inhibition of release of gastric histamine is likely to exert antisecretory and antiulcerative effects. According to Arrang et al., modification of release of the messengers of immune responses is likely to modulate the latter responses.
EP 0 338 939 discloses compounds of the formula: ##STR3##
Derwent abstract 86-273706/42 for EP 0 197 840 discloses imidazole derivatives of the formula: ##STR4## wherein R.sub.1 is H, methyl or ethyl; R is H or R.sub.2 ; and R.sub.2 is 1-6C alkyl, piperonyl, 3-(benzimidazolon-1-yl)propyl, --CZ--NHR.sub.5 or a group (i): ##STR5## wherein n is 0-3; X is a bond, O, S, NH, CO, CH.dbd.CH or a group (ii): ##STR6## R.sub.3 is H, methyl, halo, CN, CF.sub.3 or COR.sub.4 ; R.sub.4 is 1-6C alkyl, 3-6C cycloalkyl or phenyl (optionally substituted by methyl or F); Z is O, S, NH, N-methyl or N--CN; and R.sub.5 is 1-8C alkyl, 3-6C cycloalkyl (optionally substituted by phenyl), 3-6C cycloalkyl(1-3C)alkyl, phenyl (optionally substituted by methyl, halo or CF.sub.3), phenyl(1-3C)alkyl, naphthyl, adamantyl or p-toluenesulphonyl. It is disclosed that these compounds are psychotropic agents. It is also disclosed that these compounds antagonise the histamine H.sub.3 receptors and increase the speed of cerebral histamine renewal.
Derwent abstract 90-184730/24 for U.S. Pat. No. 4,925,851 discloses 2- or 4-(2-(1H-imidazol-1-yl)ethyl) piperidine compounds useful as antitumour agents for inhibiting lymphoma, sarcoma, myeloma and leukaemia. The compounds have the formula: ##STR7## wherein R is --CH.sub.2 (CH.sub.2).sub.m --Me, --CO--(CH.sub.2).sub.m --Me or --CO--CMe.sub.2 --R.sub.2 ; m is 2-18; R.sub.2 is H or Me; R.sub.1 is --(CH.sub.2 .sub.n --R.sub.3 ; n is 0-13; R.sub.3 is H, i--Pr or t--Bu; and the floating group is at the 2- or 4- position; with the proviso that (1) the sum of C atoms in R.sub.1 does not exceed 13; and (2) the sum of C atoms in R and R.sub.1 does not exceed 25.
Derwent abstract 90-180087/24 for EP 372125A discloses compounds of the formula: ##STR8## wherein X is O or S; R.sub.1 is halo, CF.sub.3, CN, NO.sub.2, OH, or 1-6C alkoxy; R.sub.2 is H, 1-6C alkyl, aryl, 7-13C aralkyl, optionally substituted amino or 5- or 6-membered N-containing ring; and R.sub.3 is 1-6C hydrocarbyl, 7-13C aralkyl or 1-13C acyl. It is disclosed that these compounds have alpha2-antagonist activity with no dopamine activity and that they are useful for treating depression and other related illnesses (e.g., anxiety or cognitive disorders).
Derwent abstract 88-309195/44 for U.S. Pat. No. 4,935,417 discloses compounds of the formula: ##STR9## wherein (according to U.S. Pat. No. 4,935,417) R.sup.1 is aryl, lower alkyl, cycloalkyl or hydrogen; R.sup.2 is aryl, lower alkyl.or hydrogen; R.sup.3 is lower alkyl, hydroxy or hydrogen; R.sub.4 is aryl or hydrogen; R.sub.5 is aryl or hydrogen; m is two or three; n is zero, one or two, provided that when R.sup.3 is hydroxy, n is one or two; and q is zero, one, two or three. U.S. Pat. No. 4,935,417 discloses that these compounds are calcium channel antagonists useful for treating mammals having a variety of disease states, such as stroke, epilipsy, hypertension, angina, migraine, arrhythmia, thrombosis, embolism and also for treatment of spinal injuries
Compounds known in the art include: ##STR10##
Known compounds in the art also include compounds of the formula: ##STR11## wherein R (Table 1)is:
TABLE 1 ______________________________________ NO. R RN CA ______________________________________ 1 --CH.sub.3 106243-44-1 106(11): 84602r 2 --CH(CH.sub.3).sub.2 106243-45-2 106(11): 84602r 3 H 106243-23-6 106(11): 84602r 4 --C(S)NHC(CH.sub.3).sub.2 CH.sub.2 C(CH.sub.3) 106243-93-0 106(11): 84602r 5 --C(O)NHCH(CH.sub.3)(phenyl) 106243-90-7 -- 6 --C(S)NH(p-chlorophenyl) 106243-85-0 -- 7 --C(O)NH(phenyl) 106243-77-0 -- 8 --C(NH)N(CH.sub.3)(cyclopropyl) 106243-73-6 -- 9 --C(S)NHCH.sub.3 106243-61-2 -- 10 --CH.sub.2 CH.sub.2 -phenyl 106243-49-6 -- 11 --CH.sub.2 CH.sub.2 -p-flurophenyl 106243-67-8 -- 12 benzyl 106243-25-8 -- ______________________________________
Additionally known compounds include: ##STR12##
In view of the art's interest in compounds which effect the H.sub.3 receptors, novel compounds having agonist or antagonist activity on H.sub.3 receptors would be a welcome contribution to the art. This invention provides just such a contribution by providing novel compounds having H.sub.3 agonist or antagonist activity.